Injection cartridges of the dual-chamber type have found a very wide use in the administering of injectable preparations which are not stable as a solution or dispersion in a liquid phase. As examples of such preparations may be mentioned certain protein compounds and hormones, such as growth hormones. These preparations are provided in a dry form, which is mixed with a liquid phase, usually water or an aqueous solution, immediately before the administering.
An injection cartridge of the dual-chamber type is generally shaped as a tubular barrel, which is divided into a front chamber and a rear chamber by means of a front piston. The front chamber contains the dry component of the injectable preparation, and is closed at its front end by a closure that permits the establishment of a liquid connection with the outside. Such a closure may be in the form of a rubber septum that may be pierced by a hollow needle for withdrawing or expelling a liquid mixture from the front chamber. The rear chamber is filled with the liquid component of the injectable preparation, usually water or an aqueous solution, and is closed at its rear end by a rear piston. When the injectable preparation is to be prepared, pressure is applied on the rear piston to move it forward. This pressure is transmitted through the essentially incompressible liquid to the front piston, such that this piston is also moved forward. By this forward movement, the front piston activates a bypass connection, such that the liquid in the rear chamber can flow over into the front chamber by the action of the forward movement of the rear piston, to be mixed with the solid component of the injectable preparation. When all of the liquid in the rear chamber has been made to flow over into-the front chamber, the front face of the rear piston will abut the rear face of the front piston. On further forward movement of the rear piston, the two pistons will act as one single piston to expel the mixed injectable preparation from the front chamber through the liquid connection mentioned above. Alternatively, the front chamber may serve as a reservoir for the mixed injectable preparation, and portions thereof may be withdrawn through the liquid connection.
The bypass connection for the liquid from the rear chamber to the front chamber may be arranged as a channel in the interior wall of the barrel of the cartridge. This channel is exposed by the front piston on its movement forward, to afford a liquid connection between the two chambers. Other arrangements are also possible.
When the injectable preparation is prepared from the two components, the injection cartridge is usually placed in a holder device provided with means for applying the pressure on the rear piston. The holder device may also be provided with means for metering and administering doses of the mixed injectable preparation.
The design and function of injection cartridges of the dual-chamber type is well-known to those skilled in the art, and need not be described here in more detail. Also, a number of the above-mentioned holder devices are well-known, and some of them are commercially available.
In the manufacture of injection cartridges of the dual-chamber type, it is, of course, of the utmost importance that sterility is maintained, so that no risk of microbial contamination of the injectable preparation will arise. However, this has been a problem with the prior art injection cartridges of the dual-chamber type.
In the prior art process for manufacture, the empty cartridges are provided with the front piston in place. The barrel of the cartridge is shaped as a cylindrical tube, which may be shaped as a bottleneck at its front end to receive the closure, and which usually consists of a rubber septum and a metal capsule having an opening in its middle. The front chamber is filled with a solution of the solid component of the injectable preparation, and the cartridge with its contents is then subjected to a freeze-drying process to evaporate the solvent and afford the component in a dry solid form. The front end of the cartridge is then closed with the closure means, and the rear chamber of the cartridge is filled with the liquid component of the injectable preparation and is closed by insertion of the rear piston.
All these operations must be carried out under aseptic or sterile conditions to assure against contamination by microorganisms. The finished cartridge cannot be heat sterilized by autoclaving, as this would degrade the sensitive solid component of the injectable preparation. The most critical of these operations is the filling of the cartridge containing the solid component with the liquid component, and the sealing of the rear chamber with the rear piston. In this operation, there is a considerable risk of microbial contamination.
It would be preferable to be able to fill the cartridge with the liquid component in the rear chamber and seal this chamber as a first step and then sterilize this assembly by autoclaving, and subsequently fill the front chamber with the solution of the solid component and carry out the freeze-drying step. However, this has not been possible, due to the fact that the cartridge with the liquid component in the rear chamber cannot be subjected to the vacuum applied during the freeze-drying step. The pressure prevailing in the rear chamber with the liquid will strive to expel the front and rear pistons from the barrel of the cartridge, and even if it is possible to secure the rear piston by some suitable holder arrangement during the freeze-drying step, this has not been possible for the front piston. Thus, during the freeze-drying step, the front piston will move forward by the influence of the pressure in the rear chamber, and will push out the solution of the solid component from the front chamber.